RU2462273C1 - Method for processing synthetic textile implanted blood contact medical devices - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically to cardiovascular surgery and may be used for modification of synthetic implanted medical devices. What is described is a method for processing synthetic textile implanted medical devices involving coating the devices with hydrogel of natural biodegradable polymers wherein the natural biodegradable polymer is presented by polysaccharide chitosan or its derivatives (carboxymethykated sulphated chitosan) in a combination with polyester-poly-3-hydroxybutyrate. The coating is dried and transferred in the water-soluble state by thermal processing at 100°C.

EFFECT: method for processing synthetic textile implanted blood contact medical devices enables providing the devices with a complex of the required properties: higher thromboresistance and antimicrobial action, zero surgical porosity and prolonged drug release.

3 cl, 1 tbl, 5 ex

Description

The invention relates to medicine, namely to cardiovascular surgery, and can be used to modify synthetic textile implantable medical devices - cardiovascular patches, blood vessel prostheses with polymer coatings containing biologically active and medicinal substances of directed action, capable of releasing into biological media for a long time .

A known method of processing synthetic textile implantable medical devices, including applying to the surface of products coatings based on substances of a protein nature - collagen, gelatin, followed by drying, transferring them to a water-insoluble state by chemical reactions with crosslinking agents, introducing heparin into the coating (Heparin bonded Dacron or Polytetrafluoroethylene for femoro-popliteal bypass: A multicenter trial. Devine and Me Collum. // J. of Vase. Surg. - 2001. - March 1 - P.533-539), silver ions (In situ revascularization with silver coated polyester grafts to treat aortic infection: early and midterm results. Batt et al. // J. Vase. Surg. - 2003. - V ol. 38. - No. 5. - P.983-989) or by pre-soaking the products in an antibiotic solution, for example rifampicin - Vascutek (Treatment of Vascular Graft Infecnion by in Situ Replasement with a Rifampincin Bonded Getlatin - Sealed Dacron Graft / Goëau-Brissoniere. Oliver et al. // J. Vase. Surg. - 1994. - Vol.19. - P.739-744).

The disadvantage of these methods is that heparin introduced into the coating is quickly washed away; silver ions are not enough to give antimicrobial properties to blood vessel prostheses, and soaking the blood vessel prostheses in antibiotic solutions immediately before implantation gives the prostheses only short-term antimicrobiality due to the rapid washing of drugs from the coating, in addition, the use of gelatin as the main modifying component of animal protein , which has species specificity and, therefore, has antigenic properties, can cause an allergic reaction tion, and can also be a breeding ground for pathogenic microorganisms. Synthetic textile products modified in this way do not have the whole range of biomedical and functional properties, namely a combination of thrombotic resistance, antimicrobiality, zero surgical porosity, and prolonged release of medicinal substances introduced into the coating.

A known method of processing synthetic textile implantable medical devices, such as blood vessel prostheses (PCS) "BASEX" and cardiovascular patches "BASEX-Patch", including applying to the surface of the product biodegradable coating based on highly purified medical grade gelatin, followed by drying of the coating, transfer coating to water-insoluble state by treatment with glutaraldehyde, introduction of a broad spectrum of antimicrobial drugs and ant preparations icoagulant and antiplatelet actions that are released from the coating for a long time (Blood vessel prostheses and cardiosurgical patches with thromboresistant, antimicrobial properties and zero surgical porosity. LA Boqueria, SP Novikova // Bulletin of the Central Scientific and Scientific Center named after AN Bakulev RAMS “Cardiovascular diseases.” - 2008. - T. 9. - No. 4. - S.5-20).

The disadvantage of this method is the use in the coating composition as the main component of an animal protein - gelatin, which has species specificity and antigenic properties, which can cause an allergic reaction, and can also be a nutrient medium for pathogenic microorganisms.

Known methods for processing synthetic textile implantable prostheses of blood vessels, including preliminary physico-chemical activation of the surface of the products, applying coatings to the surface of products based on various polysaccharides of plant and animal origin - cellulose, carboxymethyl cellulose, alginates, carrageenan, pectin, chitin (JP, No. 3254752 ( A), A61L 27/00, publ. 11/13/1991; KR, No. 920000459 (B1), A61L 27/00, publ. 01/14/1992), followed by drying and transferring the coating to a water-insoluble state by chemical reactions minutes with sodium hydroxide and monochloroacetic acid.

The disadvantage of these methods is the conduct of complex chemical surface treatment of a blood vessel using aggressive chemicals - sulfuric, perchloric acids and high-voltage plasma discharge. However, the applied coatings do not provide complete tightness of the woven base; no anticoagulant, antiplatelet and antimicrobial drugs were introduced into the coatings. Thus, coatings did not provide textile products with all the necessary set of properties - hemocompatibility, antimicrobiality, zero surgical porosity and prolonged release of drugs.

A known method of processing artificial prostheses of blood vessels (US, No. 2003163186, A61L 27/00, publ. 08.28.2003), including applying to the surface of a two-layer coating based on a polysaccharide - dextran. The coating was applied from solutions of dextran and its organic derivatives with the addition of heparin, dried and transferred to a water insoluble state by treatment with a solution of crosslinking agents with diglycidyl ether 1,4-butanediol or sodium trimethaphosphate in organic solvents.

The disadvantage of this method is that obtaining organic derivatives of dextran is possible only as a result of multi-stage organic syntheses, and when using only dextran without combining with its derivatives, it was not possible to achieve complete tightness of the vascular prostheses; after the introduction of heparin, the coating was exposed to cross-linking agents, which could lead to inactivation of heparin, in addition, information on the prolonged release of heparin was not provided; no antimicrobial medicinal substances were introduced into the coatings, and the use of organic solutions of cross-linking agents can have a negative effect on the body, and therefore a long thorough washing is required. Thus, the coating does not provide textile medical products with all the necessary set of properties - hemocompatibility, antimicrobiality, zero surgical porosity.

A known method of treating the surface of blood vessel prostheses, comprising applying a hydrogel coating based on chitosan salts, the coating being applied from solutions of chitosan in organic acids, after applying the coating to a water-insoluble state, the coating was dried at a temperature of 35-40 ° C, and the coating was introduced medicinal substances of antithrombogenic action, including heparin (JP, No. 5220213 (A), A61F 2/06, A61L 27/00, publ. 08/31/1993).

The disadvantages of this method: the resulting coating is partially water-soluble, which contributes to a strong swelling of the coating in contact with blood due to the low temperature of drying, antimicrobial agents were not introduced into the coating. Thus, the authors proposed method for treating the surface of synthetic prostheses of blood vessels does not provide the necessary set of properties - thrombotic resistance, antimicrobiality, zero surgical porosity and prolonged release of medicinal substances.

The closest technical solution, taken as a prototype, is a method of processing a polymer coating (US Patent No. US5851229, A61F 2/06, publ. 12/22/1998) of synthetic textile implantable medical devices, including applying a hydrogel coating to the surface in 4-6 layers consisting of two or more different polysaccharides, including chitosan, followed by drying at 23 ° C or 60 ° C, i.e. by transferring coatings to a water-insoluble form - for a pair of chitosan / guar gum by heat treatment at 60 ° C; glycerol or its derivatives were used as a plasticizer; only heparin was introduced as an anticoagulant, which was prolongedly released during the entire period of coating destruction, while the patent did not contain data on the timing of destruction.

The disadvantages of this method are as follows: of the 57 variants of combinations of various components, only 1 variant of the coating based on chitosan in combination with guar gum made it possible to achieve zero permeability; a temperature of 60 ° C was used to convert the coatings into a water-insoluble form for a pair of chitosan / guar gum, however, under these conditions it is difficult to obtain a coating structure that provides zero permeability, as a result of which a multilayer, 6-fold coating was applied, in addition, no drug substances were used, providing antimicrobiality of the coating, and to impart thrombotic resistance, only one component was introduced into the coating - the anticoagulant - heparin.

The technical result of this invention is to reduce the surgical porosity of textile implantable medical devices to zero, increase their thrombotic resistance and antimicrobiality, increase the content of drugs in the coating applied to the products, and prolong their release.

The proposed method of modifying textile materials is as follows.

Prepare polymer solutions:

Solution A: 0.5-4.0 wt.% - a solution of poly-3-hydroxybutyrate (PHB) (chemically pure) with a molecular weight of 600-900 kDa in chloroform with the addition of ciprofloxacin - 30% by weight of the polymer and dipyridamole -30% by weight of the polymer.

Solution B: 4-6 wt.% - a solution of chitosan or its derivatives (chemically pure) with a molecular weight of 200-300 kDa in 1-3 wt.% - acetic acid.

The textile base (medical canvas for cardiosurgical patches, vascular prosthesis, suture thread) is treated with polymer A solution, dried at room temperature, then treated in solution B and dried at room temperature to constant weight. The modified textile base is heat treated at a temperature of 100 ° C for 1-1.5 hours, then treated with a heparin solution with a concentration of 500 IU / ml, followed by drying. The introduction of ciprofloxacin, dipyridamole and a plasticizer in the chitosan layer is carried out by sorption from their solution with a concentration of 1-2 mg / ml.

The technical result is achieved in that in a method for processing synthetic textile implantable medical devices, including applying a hydrogel coating to the surface of products based on natural biodegradable polymers, followed by drying the coating, transferring the coating to a water-insoluble state by heat treatment, and introducing biologically active and medicinal substances and a plasticizer into the coating , as a natural biodegradable polymer, chitosan polysaccharide or its derivative is used e (sulfonated chitosan, carboxymethylated) in combination with a natural biodegradable polyester-poly-3-hydroxybutyrate, they are transferred to a water-insoluble state at a temperature of 100 ° C, and when biologically active and medicinal substances are introduced into the coating, heparin is used in combination with ciprofloxacin and dipyridamole, moreover, the coating consists of 2 layers and it is formed in layers, the first layer is polyester poly-3-hydroxybutyrate with a molecular weight of 600-900 kDa, which is applied from a solution of poly-3-hydroxybutyrate in chloroform with a concentration of 0.5-4 wt.%, the second layer is chitosan polysaccharide or its derivatives with a molecular weight of 200-300 kDa, which is applied from an acetic acid solution of chitosan with a concentration of 4-6 wt.%, drugs are introduced into both coating layers, moreover, 30 wt.% of ciprofloxacin and 30 wt.% dipyridamole are added to poly-3-hydroxybutyrate in the preparation of a solution of poly-3-hydroxybutyrate in chloroform, the introduction of biologically active and medicinal substances into the chitosan layer is carried out after heat treatment sequentially: first, sorption from solution heparin in a concentration of 500 IU / ml, followed by drying, followed by sorption of ciprofloxacin and dipyridamole of their solutions at a concentration of 1-2 mg / ml.

Chitosan is the most promising natural polymer in terms of biocompatibility and in connection with its film-forming properties. It is degraded in the body to non-toxic substances, which are metabolites of the body itself (N-acetylglucosamine, glucosamine). The use of chitosan polysaccharide or its derivatives (sulfonated chitosan, carboxymethylated) in combination with the natural polyester - poly-3-hydroxybutyrate (PHB) allows to achieve zero permeability, to provide increased, double deposition of drugs, due to the presence of a 2-layer structure of polymers of different nature .

The first layer - PHB is a hydrophobic, slightly swellable polymer and has a reduced rate of release of medicinal substances, which ensures their release in the long term.

The second layer - a swelling hydrogel layer of chitosan provides complete sealing of the textile base and the allocation of the necessary initial therapeutic quantities of drugs with greater speed in the initial stages.

PHB is applied from a solution in chloroform with a concentration of PHB 0.5-4 wt.%. A concentration below 0.5 wt.% Is impractical due to insufficient film-forming ability and the impossibility of introducing the required amount of medicinal substances, and a solution with a concentration above 4 wt.% Has a very high viscosity, it is difficult to apply to the surface of the product. Medicinal substances (PH) are introduced into PHB — ciprofloxacin, dipyridamole in quantities of 30 wt%, this is the maximum amount of drug that is compatible with the polymer, a larger amount of drug causes loosening of the polymer structure, and it loses its film-forming properties.

Acetic acid solution of chitosan with a concentration of 4-6 wt.% Is applied to the first layer of PHB. A concentration below 4 wt.% Does not provide zero water permeability, and a solution with a concentration above 6 wt.% Has a very high viscosity, it is difficult to apply it to the surface of a product treated with PHB.

When converting coatings to a water-insoluble state, heat treatment is used in combination with subsequent treatment with heparin, heparin is not only an anticoagulant, but also a crosslinking agent, forming a water-insoluble polyelectrolyte complex with chitosan, and the subsequent introduction of dipyridamole into the chitosan layer promotes additional immobilization of heparin and more excretion than in the case of using only one heparin. To convert the coating into a water-insoluble form, heat treatment is used at a temperature of 100 ° C. Translation into a water-insoluble state is necessary only for the upper layer - chitosan (PHB is not a water-soluble polymer). At this temperature, the most complete transition of the amino groups of chitosan to acetamide groups occurs, which contributes to the water insolubility of the coating, and a coating forms with specified biodegradation periods.

The introduction of drugs into the chitosan layer is carried out by sorption from their solutions with concentrations: for heparin - 500 IU / ml, for ciprofloxacin and dipyridamole - 1-2 mg / ml. The selected drug concentrations are optimal for their maximum sorption. At a heparin concentration below 500 IU / ml and concentrations of ciprofloxacin and dipyridamole below 1 mg / ml, the chitosan layer adsorbs an insufficient amount of drug, and at a drug concentration above the selected, incompatibility with the polymer is observed.

To impart elasticity to the coating, glycerol and its derivatives were introduced as a plasticizer.

The amount of drugs introduced into the PHB layer was determined by weighing the difference between the weight of the product before and after coating, knowing the mass ratio of the polymer and the mixture of drugs, and the amount of drugs in the chitosan layer was determined spectrophotometrically using a Shimadzu device in the UV and visible regions using calibration curves.

The amount of released drug substances in the coating and the prolongation of their release were estimated spectrophotometrically, placing the product in physiological saline (model medium).

Antimicrobial properties were evaluated by microbiological tests using the disk diffusion method. (Guidelines for determining the sensitivity of microorganisms to antibiotics by diffusion in agar using discs. - M., 1983. - 16 p.)

The destruction of the coatings was studied in model media (sterile, acidified physiological saline) at a temperature of 37 ° C.

The water permeability of the modified materials was determined at a pressure of 200 mm Hg. (GOST R 51566-2000 "Prostheses of blood vessels. General technical requirements. Test methods").

The invention is illustrated by examples.

Example 1

Solutions of polymers are prepared for subsequent application to the textile base of a blood vessel prosthesis:

Solution A: 2% solution of PHB (chemically pure) with a molecular weight of 900 kDa in chloroform with the addition of ciprofloxacin - 30% by weight of the polymer and dipyridamole 30% by weight of the polymer.

Solution B: 4% solution of chitosan (chemically pure) with a molecular weight of 300 kDa in 2% acetic acid.

A sample of a tissue vascular prosthesis is sequentially treated with solutions of polymers A and B, sequentially dried at room temperature to constant weight. The chitosan layer is transferred to a water-insoluble state in the following way: the modified textile base is heat treated at a temperature of 100 ° C for 1.5 hours, followed by treatment with a heparin solution with a concentration of 500 IU / ml and drying. The introduction of ciprofloxacin, dipyridamole and a plasticizer - glycerol into the chitosan layer is carried out by sorption from their total solution with a concentration of 2 mg / ml.

The modified vascular prosthesis has zero water permeability, contains a large number of drugs in the coating - 41.0 mg / g of coating, drugs are released continuously - from the chitosan layer the antimicrobial drug is released within 14 days, and from the PHB layer more than 30 days, an anticoagulant and antiplatelet agent platelets are secreted from both layers for more than 50 days. The chitosan coating layer in a model medium is destroyed within 60-65 days.

Example 2

Prepare polymer solutions:

Solution A: 0.15% solution of PHB (chemically pure) with a molecular weight of 900 kDa in chloroform with the addition of ciprofloxacin - 30% by weight of the polymer and dipyridamole 30% by weight of the polymer.

Solution B: 4% solution of chitosan (chemically pure) with a molecular weight of 300 kDa in 2% acetic acid.

A sample of a tissue vascular prosthesis is sequentially treated with solutions of polymers A and B, sequentially dried at room temperature to constant weight. The chitosan layer is transferred to a water-insoluble state in the following way: the modified textile base is heat treated at a temperature of 100 ° C for 1.5 hours, followed by treatment with a heparin solution with a concentration of 500 IU / ml and drying. The introduction of ciprofloxacin, dipyridamole and a plasticizer - glycerol into the chitosan layer is carried out by sorption from their total solution with a concentration of 2 mg / ml.

The modified vascular prosthesis has zero permeability, but it contains about 2 times less drugs than in example 1 - 25.5-26.0 mg / g of coating. Medicinal substances are released faster than in example 1, the antimicrobial drug is completely released within 15 days, and the antiplatelet agent in less than 30 days.

Example 3

Prepare polymer solutions:

Solution A: 4% solution of PHB (chemically pure) with a molecular weight of 900 kDa in chloroform, with the addition of ciprofloxacin - 30% by weight of the polymer and dipyridamole 30% by weight of the polymer.

Solution B: 5% solution of sulfonated chitosan (chemically pure) with a molecular weight of 300 kDa in 2% acetic acid.

A sample of a tissue vascular prosthesis is sequentially treated with solutions of polymers A and B, sequentially dried at room temperature to constant weight. The sulfonated chitosan layer is converted into a water-insoluble state in the following way: the modified textile base is heat treated at a temperature of 100 ° C for 1.5 hours, followed by treatment with a 500 IU / ml heparin solution and drying. The introduction of ciprofloxacin, dipyridamole and a plasticizer - glycerol in a layer of sulfonated chitosan is carried out by sorption from their total solution with a concentration of 2 mg / ml.

The modified vascular prosthesis has zero water permeability, contains a large number of drugs in the coating 47.8 mg / g of coating, drugs are released continuously - from the chitosan coating layer, the antimicrobial drug is released within 14 days, and from the PHB layer more than 30 days, the platelet antiplatelet is released from both layers for more than 50 days. The chitosan coating layer in a model medium is destroyed within 70 days.

Example 4

Prepare polymer solutions:

Solution A: 0.25% solution of PHB (chemically pure) with a molecular weight of 900 kDa in chloroform, with the addition of ciprofloxacin - 30% by weight of the polymer and dipyridamole 30% by weight of the polymer.

Solution B: 4% solution of chitosan (chemically pure) with a molecular weight of 300 kDa in 2% acetic acid.

A sample of a tissue vascular prosthesis is sequentially treated with solutions of polymers A and B, sequentially dried at room temperature to constant weight. The chitosan layer is transferred to a water-insoluble state in the following way: the modified textile base is heat treated at a temperature of 100 ° C for 1.5 hours, followed by treatment with a heparin solution with a concentration of 500 IU / ml and drying. The introduction of ciprofloxacin, dipyridamole and a plasticizer - glycerol into the chitosan layer is carried out by sorption from their total solution with a concentration of 2 mg / ml.

The modified vascular prosthesis has zero water permeability, contains 31.5 mg / g of coating in the coating of drugs, drugs are released continuously - from the chitosan coating layer, the antimicrobial drug is released within 20 days, and from the PHB layer for more than 25 days, platelet antiplatelet is released from both layers for more than 35 days. The chitosan coating layer in a model medium is destroyed within 65 days.

Example 5

Prepare polymer solutions:

Solution A: 2% solution of PHB (chemically pure) with a molecular weight of 900 kDa in chloroform with the addition of ciprofloxacin - 30% by weight of the polymer.

Solution B: 4% solution of chitosan (chemically pure) with a molecular weight of 300 kDa in 2% acetic acid.

A sample of a tissue vascular prosthesis is sequentially treated with solutions of polymers A and B, sequentially dried at room temperature to constant weight. The chitosan layer is transferred to a water-insoluble state in the following way: the modified textile base is heat treated at a temperature of 100 ° C for 1.5 hours, followed by treatment with a heparin solution with a concentration of 500 IU / ml and drying. The introduction of ciprofloxacin and a plasticizer - glycerol into the chitosan layer is carried out by sorption from their total solution with a concentration of 2 mg / ml. Dipyridamole was not administered.

The modified vascular prosthesis has zero water permeability, contains 37.0 mg / g of coating in the coating of drugs, drugs are released continuously - from the chitosan coating layer the antimicrobial drug is released within 14 days, and from the PHB layer more than 35 days, the platelet antiplatelet is released in 15 day due to the fact that dipyridamole is not added to the coating.

The chitosan coating layer in a model medium is destroyed within 65 days.

For clarity, the results are listed in table 1.

Thus, the table shows that the use of the chitosan polysaccharide and its derivatives (sulfonated chitosan, carboxymethylated), in combination with the natural polyester - poly-3-hydroxybutyrate (PHB) allowed to achieve zero permeability, to provide increased deposition of drugs due to the presence of 2 -layer structure of polymers of different nature, and the subsequent introduction of dipyridamole (examples 1-4) into the chitosan layer contributed to the additional immobilization of heparin and its more prolonged release, than in reducing the number of drugs in the coating they will stand out from the coating without providing prolonged therapeutic effect (Examples 2 and 5).

Therefore, the proposed method for processing synthetic textile medical products intended for contact with blood allows you to give products a complex of necessary properties: increased thrombosis resistance and antimicrobiality, zero surgical porosity and prolonged release of drugs.

Claims (3)

1. A method of processing synthetic textile implantable medical devices, including applying a hydrogel coating to the surface of products based on natural biodegradable polymers, followed by drying the coating, transferring the coating to a water-insoluble state by heat treatment, and introducing biologically active and medicinal substances and a plasticizer into the coating, characterized in that as a natural biodegradable polymer, chitosan polysaccharide or its derivatives (sulfonated zan, carboxymethylated) in combination with a natural biodegradable polyester - poly-3-hydroxybutyrate, they are transferred to a water-insoluble state at a temperature of 100 ° C, and when biologically active and medicinal substances are introduced into the coating, heparin is used in combination with ciprofloxacin and dipyridamole. 2. The method according to claim 1, characterized in that the coating consists of 2 layers and it is formed in layers, the first layer being polyester poly-3-hydroxybutyrate with a molecular weight of 600-900 kDa, which is applied from a solution of poly-3-hydroxybutyrate in chloroform with a concentration of 0.5-4 wt.%, the second layer is a polysaccharide-chitosan or its derivatives with a molecular weight of 200-300 kDa, which is applied from an acetic acid solution of chitosan with a concentration of 4-6 wt.%. 3. The method according to claim 1, characterized in that the medicinal substances are introduced into both coating layers, with 30 wt.% Ciprofloxacin and 30 wt.% Dipyridamole added to the solution of poly-3-hydroxybutyrate in chloroform, and the introduction of medicinal substances into the chitosan layer after heat treatment is carried out sequentially: first by sorption from heparin solutions with a concentration of 500 IU / ml, followed by drying, then by sorption of ciprofloxacin and dipyridamole from their solutions with a concentration of 1-2 mg / ml.